Alveolar-arterial oxygen gradient: An early marker to predict the severity of community-acquired pneumonia in children

To study the clinical significance of alveolar-arterial oxygen gradient (PA-aO2) for children with community-acquired pneumonia (CAP). A prospective study was carried out from January 2020 to June 2023, Overall, 100 patients were included in the study, 35 had severe pneumonia, whereas, 65 had non-severe pneumonia. Clinical and laboratory data were retrospectively collected at the time of hospital admission and during hospitalization. Patients were divided into severe and non-severe groups. PA-aO2 was significantly higher among children with severe pneumonia, as determined by WHO, PRESS (P < .001). PA-aO2 was significantly higher among children with mechanical ventilation, shock, sepsis, and mortality. Receiver operating characteristic curve (ROC) analysis for PA-aO2 showed that the area under the curve was 0.76 (P value < .05), with a sensitivity of 84.3% and a specificity of 67.9%. Our study suggests that PA-aO2 level has a predictive value for detecting community-acquired pneumonia severity in children.


Introduction
Community-acquired pneumonia (CAP) in childhood is defined as an acute infection of the pulmonary parenchyma in a child caused by a pathogen acquired outside the hospital, that is, in the community. [1,2]It is an important cause of morbidity in developed countries and an important cause of morbidity and mortality in developing countries. [3]The World Health Organization estimates that approximately 2 million children under the age of 5 years die of pneumonia each year worldwide; the majority of these deaths occur in developing countries. [4,5]The mortality rate in developed countries is less than 1 per 1000 per year. [1,3]evertheless, community-acquired pneumonia is associated with enormous costs either directly through medical expenses or indirectly through loss of working hours by parents of sick children. [6]herefore, one of the main challenges in the management of CAP is to stratify patients early according to their risk of clinical deterioration.alveolar-arterial oxygen gradient (P A-a O 2 ) is defined as the difference between the alveolar and arteriolar concentration of oxygen, and it is a highly accurate index of pulmonary function. [7]This work attempted to investigate the value of P A-a O 2 in the prediction of CAP severity in pediatric patients.

Materials and methods
A retrospective study was performed in The First People's Hospital of Linping District.All CAP patients (35 severe pneumonia, 65 non-severe pneumonia) who were admitted to the pediatric department between January 2020 to June 2023 were enrolled in the study.The study was conducted on children with pneumonia from the age of one month to 14 years.Two patient groups were recruited: the first included children hospitalized with a diagnosis of severe CAP while the second included children with non-severe CAP.All children of their parent gave their consent to participate in the study.The first People's Hospital of Linping District Ethics Committee approved the study (approval number: linping2023044).
Inclusion criteria were age beyond 1 month up to 14 years and patients diagnosed with CAP, present signs and symptoms of pneumonia.This was confirmed by the radiological finding of a consolidation. [6]Exclusion criteria's were: severe immune dysfunction; Incomplete clinical data; and Automatic discharge.
We used three severity scores in our research, that is the Respiratory Index of Severity Score (RISC), [8] the Predisposition, Insult, Response, Organ dysfunction modified (PIROm) [9] and the Pediatric Respiratory Severity Score (PRESS). [10]ediatric Intensive Care Unit (PICU) admission criteria were oxygen saturation (SPO 2 ) < 92%, signs of shock, the need for mechanical ventilation, respiratory failure, and altered mental status. [1]he primary outcome measure was the occurrence of the length of PICU stay during the hospital.The secondary outcome measures included shock, mechanical ventilation, and sepsis.

Data collection
Clinical and laboratory parameters of patients were collected from the electronic medical record system.The laboratory findings were analyzed within 3 hours after admission including arterial blood gas analysis and, complete blood count.Furthermore, the severity of pneumonia were determined by mortality predictive scores, including the RISC and the PIROm for respiratory infections, evaluated by the PRESS to determined the severity of respiratory tract infections, clinical criteria and radiological and laboratory data were collected to evaluate score.

Data analyses and statistics
Statistical analyses were performed using SPSS for Windows Version 26 (Chicago, USA).Statistical data are expressed as n (%), and the χ 2 test.Normally distributed measures are expressed as mean ± standard deviation, and the t test for 2 independent samples was used for comparison between groups.The P A-a O 2 was evaluated by the receiver operating characteristic (ROC) curve.The independent risk factors for PICU admission were evaluated.Differences were considered statistically significant at P < .05.

Result
The studied patients consisted of 100 children with CAP, including 65 (65%) with simple pneumonia and 35 (35%) with severe pneumonia.Their main demographic and clinical characteristics are shown in Table 1.Pathogenic bacteria were isolated from blood cultures in only 12 patients (34.3%).Clinical indicators of pneumonia severity, such as the need for mechanical ventilation, shock, and sepsis, presented in the PICU admitted group as 28.6%, 14.3%, and 25.7%, respectively.All patients of the PICU admitted group and 24.6% of patients of the simple pneumonia group had SIRS criteria.These clinical indicators were secondary to CAP.P A-a O 2 was significantly elevated among PICU admitted compared with simple pneumonia [105.4 (79.4-142.5)]versus [33.8 (23.4-65.8),P < .05)].Acidosis was significantly higher in PICU admitted than in simple pneumonia Table 2.
P A-a O 2 was significantly higher in patients with severe pneumonia complicated with shock, and sepsis and was also higher among those needing mechanical ventilation and who did not survive Table 3.
Multivariate regression analysis revealed that P A-a O 2 level, hospital-free days, mechanical ventilation need, shock, and sepsis were independent risk factors for the occurrence of severe pneumonia with odds ratios 6.58, 3.86, 2.85, 2.64, and 1.27, respectively Table 4.The ROC curve analysis for P A-a O 2 level as a predictor of pneumonia severity showed that the area under the curve was 0.76 (P value < .05),At a cutoff point (94.6) with a sensitivity of 84.3%, a specificity of 67.9%, positive predictive value of 85.6%, and negative predictive value of 88.9% Figure 1.

Discussion
Pneumonia is one of the major causes of hospitalization in children, and CAP plays an important role in the development of pneumonia in children. [11]CAP is mostly self-limiting, but it may also cause life-threatening illness with respiratory distress and multiple organ involvement even in immunocompetent individuals.Severe CAP is characterized by severe respiratory system involvement, multiple system complications, and high mortality. [12]In this retrospective study of 25 subjects diagnosed with severe CAP at our hospital, we preliminarily analyzed the mortality risk factors in children with severe CAP and revealed that P A-a O 2 level, hospital-free days, mechanical ventilation need, shock, and sepsis were independent risk factors for the occurrence of severe pneumonia.
Recently, a study by de Roos et al supported the use of P A- a O 2 in association with chest computed tomography scanning to identify patients in need of hospitalization at an early stage. [13][16] The results of the present study align with the data of the consulted literature and suggest that a high P A- a O 2 is a severity marker of severe CAP.Among children with severe CAP, ventilator-blood flow ratio disorders are present with decreased lung ventilation and ventilation function.Studies have shown that P A-a O 2 can more sensitively reflect lung ventilation function than other commonly used indexes such as oxygen partial pressure and oxygenation index. [16]P A-a O 2 is the difference between alveolar and arterial oxygen partial pressure, and its level is related to ventilation-blood flow ratio, gas dispersion, and anatomic  Data are presented as mean ± standard deviation, n (%), or median (interquartile range).CRP = C-reactive protein, P A-a O 2 = Alveolar-arterial oxygen gradient, PCT = procalcitonin, WBC = white blood cell.
shunt. [17]In the case severe CAP with stable pulmonary perfusion, the higher the P A-a O 2 , the worse the pulmonary gas exchange, and the decreased diffusion function. [17]linical indicators of pneumonia severity, such as the need for mechanical ventilation, shock, and sepsis, presented in PICU admitted as 24%, 12%, and 32% respectively.Patients who experienced these clinical indicators were consequent to the development of CAP, which is the most common cause of sepsis in many studies. [18,19]Approximately 40% to 50% of patients with sepsis present respiratory sources of infection. [20]In addition, a large adult study suggested that severe sepsis is a common feature in CAP (48% of hospitalized patients), with 4.5% of patients developing septic shock. [21]egarding P A-a O 2 as a potential prognostic biomarker for pneumonia outcome, we showed that the highest P A-a O 2 level was found among the patients who died.Pipitone G et alnoted that higher circulating levels of P A-a O 2 are associated with higher mortality risk in patients with pneumonia due to the COVID-19 Virus. [22]

Conclusion
In conclusion, P A-a O 2 has a certain sensitivity and specificity for predicting the occurrence of CAP, and have important clinical application value.

Figure 1 .
Figure 1.ROC analysis of P A-a O 2 for predicting CAP.CAP = communityacquired pneumonia, P A-a O 2 = Alveolar-arterial oxygen gradient, ROC = receiver operating characteristic curve.

Table 1
Baseline characteristics of the studied population.
Data are presented as mean ± standard deviation, n (%), or median (interquartile range).BMI = body mass index, PICU = Pediatric Intensive Care Unit.

Table 2
Laboratory and radiological characteristics of the studied groups.

Table 3 P
A-a O 2 in relation to patients' complications and outcomes.P A-a O 2 , median (IQR) P Data are presented as median (interquartile range).SIRS systemic inflammatory response syndrome

Table 4
Multivariate regression analysis of risk factors for pneumonia severity.